The Carbonic Anhydrases: Current and Emerging Therapeutic Targets

Description

This volume assembles and integrates the wealth of diverse information that is now accumulating in this burgeoning field. The existing and potential therapeutic applications of targeting CA cover a remarkably wide-range of diseases and disorders and have generated increasing and extensive interest in recent years. Its inter-disciplinary approach embraces both the most up-to-date therapeutic application of CA-targeting and the latest research data that will provide a platform for the development of novel applications. The interested audience comprises scientists and clinicians from many relevant disciplines within science and medicine. Dedication to Richard Tashian Preface Contents 1 The Carbonic Anhydrases in Health and Disease References 2 Carbonic Anhydrase Isozymes as Diagnostic Biomarkers and Therapeutic Targets 2.1 Short Introduction of Mammalian Carbonic Anhydrases 2.2 CA II as a Biomarker 2.3 CA IX as a Biomarker 2.4 CA IX Immunoassay Data 2.5 CA XII in Cancer 2.6 Carbonic Anhydrases as Therapeutic Targets 2.7 Concluding Remarks References 3 Targeting Carbonic Anhydrases in Cardiovascular and Pulmonary Disease 3.1 Introduction 3.2 Carbonic Anhydrase Isozymes and Activity in the Cardiopulmonary System 3.3 Effects of CA Inhibitors Independent of CA Inhibition 3.4 CA Functions in the Normal Heart 3.4.1 CO2 Elimination 3.4.2 Cardiac pH Homeostasis 3.4.3 Metabolism-Perfusion Matching 3.4.4 Fatty Acid/Lactate Uptake 3.4.5 Myocardial Contractility and Calcium Mobilization 3.5 CA Functions in the Normal Lung 3.5.1 Alveolar Carbon Dioxide Elimination 3.5.2 Lung Fluid Exchange and pH Regulation 3.5.3 Ventilation-Perfusion Matching 3.5.4 Pleural Fluid Composition and Turnover 3.6 Carbonic Anhydrase Inhibitors and Cardiovascular Disease 3.6.1 Systemic Hypertension 3.6.2 Cardiac Hypertrophy and Heart Failure 3.6.3 Coronary Artery Disease and Myocardial Infarction 3.7 Carbonic Anhydrase Inhibitors in Pulmonary Disease 3.7.1 Chronic Obstructive Pulmonary Disease (COPD) 3.7.2 Chronic Cough 3.7.3 Pulmonary Hypertension (PH) 3.7.4 Lung Ischemia–Reperfusion Injury 3.8 Conclusions References 4 Carbonic Anhydrase Inhibitors in Ophthalmology: Glaucoma and Macular Oedema 4.1 Introduction 4.2 Carbonic Anhydrase Inhibitors in Glaucoma 4.2.1 Systemic Carbonic Anhydrase Inhibitors 4.2.2 Topical Carbonic Anhydrase Inhibitors 4.2.3 Carbonic Anhydrase Inhibitors in Ocular Perfusion 4.3 Carbonic Anhydrase Inhibitors in Macular Oedema 4.3.1 Systemic Carbonic Anhydrase Inhibitors 4.3.2 Topical Carbonic Anhydrase Inhibitors References 5 Targeting Carbonic Anhydrase Isozymes in the Treatment of Neurological Disorders 5.1 Expression and Function of Enzymatically Active Carbonic Anhydrases in the Nervous System 5.2 CA Inhibitors in the Treatment of Neurological Diseases 5.3 CA Inhibitors in the Treatment of Acute High-Altitude Illness 5.4 CA Inhibitors in the Treatment of Pseudotumor Cerebri 5.5 CA Inhibitors in the Treatment of Brain Edema 5.6 CA Inhibitors in the Treatment of Epilepsy 5.7 Carbonic Anhydrase-Related Proteins (CARPs) 5.8 Localization and Role of CARP VIII 5.9 Distribution and Role of CARP X 5.10 Distribution and Role of CARP XI 5.11 Concluding Remarks References 6 Potential of Carbonic Anhydrase Inhibitors in the Treatment of Oxidative Stress and Diabetes 6.1 Introduction 6.2 Oxidative Stress and Diabetes 6.3 Retinal Pericytes and Metabolic Activity 6.4 Metabolic Activity, Oxidative Stress, and Diabetic Retinopathy 6.5 Carbonic Anhydrases 6.6 Mitochondrial Carbonic Anhydrases and Oxidative Stress 6.7 Carbonic Anhydrase Inhibitors and Prevention of Diabetic Retinopathy 6.8 Conclusions References 7 An Overview of Carbonic Anhydrase-Related Neoplasms 7.1 Introduction 7.2 Expression of Cytoplasmic CA Isoforms in Neoplasms 7.3 Expression of Mitochondrial CA Isoforms in Cancer 7.4 Expression of Membrane-Bound and Secreted CA Isoforms in Cancer 7.5 Expression of Inactive CA Isoforms in Cancer 7.6 Carbonic Anhydrase-Related Neoplasms 7.7 Conclusions References 8 Carbonic Anhydrase IX Interactome and the Regulation of Cancer Progression 8.1 Tumour Microenvironment and Hypoxia 8.2 CAIX—regulation, Protein and Function 8.3 Overview of the CAIX Interactome 8.4 CAIX in Metastasis 8.4.1 CAIX and Cell–cell De-Adhesion 8.4.2 CAIX and Cell Migration 8.4.3 Invadopodia-Mediated Cell Invasion 8.5 Amino Acid Transporters and CAIX 8.6 CAIX and Unfolded Protein Response 8.7 Summary and Therapeutic Implications References 9 Carbonic Anhydrase IX: Current and Emerging Therapies 9.1 Introduction 9.2 Carbonic Anhydrase IX Imaging 9.2.1 CAIX Imaging in RCC 9.2.2 CAIX Imaging in Non-RCC 9.3 Intraoperative Imaging 9.4 CAIX-Directed Radioimmunotherapy 9.5 Carbonic Anhydrase IX Immunotherapy 9.6 Conclusion and Future Perspectives References 10 Carbonic Anhydrase Inhibitors: Designing Isozyme-Specific Inhibitors as Therapeutic Agents 10.1 Introduction: Classical CA Inhibitors (CAIs) 10.2 CA Inhibition Mechanisms and the Drug Design 10.3 Strategies for Obtaining Isoform-Selective CAIs 10.4 Conclusions References 11 Carbonic Anhydrase Inhibitors: Identifying Therapeutic Cancer Agents Through Virtual Screening 11.1 Virtual Screening in Drug Discovery 11.2 Virtual Screening Studies Identifying Novel Carbonic Anhydrase Inhibitors 11.3 Retrospective Virtual Screening Studies Using Carbonic Anhydrases as Target Receptors References 12 Targeting Carbonic Anhydrase IX in Tumor Imaging and Theranostic Cancer Therapy 12.1 Introduction 12.2 Targeting CA-IX as a Biomarker of Tumor Hypoxia 12.3 Methods for Detecting Tumor Hypoxia 12.4 CA-IX Expression in Clear Cell Renal Cell Carcinoma 12.5 Monoclonal Antibodies 12.5.1 Imaging with G250/cG250 12.5.2 Radioimmunotherapy with G250/cG250 12.5.3 Dual Modality Imaging with cG250 12.6 Peptides and Affibodies 12.7 Small Molecule Inhibitors 12.7.1 Net Charge 12.7.2 Multivalence and Size 12.7.3 Radiometal Chelator Complex 12.8 Perspectives and Conclusion References Index